Inhibition profile

The drug inhibition profile of (+)3H-SKF-10,047 binding is similar in many ways to that of (+)3H-3-PPP binding, but has some important differences. While pentazocine and SKF-10,047 are both potent inhibitors of (+)3H-SKF-10,047 binding, haloperidol and (+)3H-3-PPP inhibit only a portion of total specific (+)3H-SKF-... 

Jenkins, K.M. et al. 2004. Automated high throughput ADME assays for metabolic stability and cytochrome P450 inhibition profiling of combinatorial libraries. J. Pharm. Biomed. Anal. 34 989. 

Kumar, V., Wahlstrom, J.L., Rock, D.A., Warren, C.J., Gorman, L.A. and Tracy, T. S. (2006) CYP2C9 inhibition impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metabolism and Disposition. 34 (12), 1966-1975. 

Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996 50(3) 209-215. 

Fig. 16.1. Progress of two rounds of Chk1 targeted libraries. Cpd-1 is the original HTS hit with a broad kinase inhibition profile and based on which the first round library was designed and synthesized. 1808-1 is the best hit from the first round targeted library with improved kinase selectivity profile, based on which the second round library was designed and synthesized. 1819-1 is the best lead with improved potency, kinase selectivity, and solubility. Co-crystal structures of Chkl kinase domain and corresponding lead compounds were solved and extensively utilized in structure-based singleton and library designs. For details of the X-ray co-Crystal structures, please refer to the publications from Ming and et al (4a) and Foloppe and et al for details (4b).

Another kinetic profile, substrate inhibition, occurs when the velocity from ESS is lower than that of ES (Fig. 5). In this case, the saturation curve will increase to a maximum and then decrease before leveling off at Vm2. For the P450 enzymes, Vm2 is usually not zero when sub-millimolar concentrations of substrate are involved. This observation suggests that ESS still has some activity. If substrate inhibition occurs at very high substrate concentrations, non-active-site interactions should be suspected. Substrate inhibition profiles are easily identified, provided that the observed concentration range is appropriate and Kmi is not much smaller than Km2 (Fig. 5). However, determining the kinetic constants in Eq. (10) requires... 

Transon C, Leemann T, Vogt N, et al. In vivo inhibition profile of cytochrome P450 (tb) (CYP2C9) by (+/-)-fluvastatin. Clin Pharmacol Ther 1995 58 412-417. 

Fig. (6). COX-1 ( ) and COX-2 ( ) enzymes inhibition profile of HTP fractions from Camellia sinensis.

Fig. (11), COX inhibition profile of HTP fractions from organic extract of the roots from Scutellaria baicaensis.

Hinokitiol is a tropolone type natural compound isolated from the wood of Chymacyparis taiwanesis. The compound has been utilized as a natural antimicrobial agent in hair tonics, toothpastes, cosmetics and food supplements. Hinokitiol was evaluated on five different arachidonic acid metabolic pathways for the mechanism of action of anti-inflammatory effects. It has been found to be a potent inhibitor with IC50 values of 0.1 pM against platelet-type 12-LOX and 50 pM against leukocyte-type 12-LOX. It also inhibited soybean 5-LOX enzyme (IC50 = 17 pM). However, hinokitiol had almost no effects on COX-1 and COX-2 enzymes. Similar inhibition profiles were also observed on synthetic tropolone derivatives [168]. 

Protease Classification. In order to rationally design an inhibitor for a protease it is first necessary to place it into one of four families of proteases (see Table V). For a new enzyme, a study of its inhibition profile with a series of general protease inhibitors is sufficient to classify it into one of the four families. The inhibitors usually used are diiso-propylphosphofluoridate (DFP) or phenylmethane sulfonyl fluoride (PMSF) for serine proteases, 1,10-phenanthroline for metalloproteases, thiol reagents such as iodoacetate or N-ethylmaleimide for thiol proteases, and pepstatin or diazo compounds such as diazoacetyl-norleucine methyl ester for carboxyl proteases. 

Whereas small molecules employ p450 activation/inhibition profiles to elucidate metabolic interactions/antagonisms, there is no comparable tool to model the potential interactions of multiple biologies or between biologies and cytotoxics. To assess potential interactions between a protein therapeutic and cytotoxic chemotherapy SOC, one approach is to conduct a single-dose PK interaction study to assess the impact of the protein therapeutic on the PK of the SOC cytotoxics in a pharmacologically relevant species (Table 25.2 [7,8]). The objective of these studies is to determine whether the protein therapeutic has an effect on the PK, particularly the peak concentration (Cmax) and/or time of peak concentration (Tmax) that might result in potentiation of the toxicity of the cytotoxic, or reduced efficacy associated with decreased exposure. 

Figure 12.2 Pharmacodynamic profiles of NPI-0052 and bortezomib after a single IV administration in mice or rats. (A) Inhibition of CT-L, T-L and C-L 205 proteasome activities in packed whole blood (PWB) lysates after a single IV administration of NPI-0052 (0.15 mg/kg) or bortezomib (1 mg/kg) in mice. NPI-0052 exhibits a broader and longer 20>S proteasome inhibition profile than bortezomib.14 (B) CT-L 205 proteasome activity recovers more quickly in peripheral blood mononuclear cell (PBMQ lysates compared with PWB lysates after NPI-0052 administration to rats at 0.05 mg/kg or 0.1 mg/kg.

Our initial findings that NPI-0052 inhibited all three proteolytic functions of the IDS proteasome vide supra) led us to compare its profile with other proteasome inhibitors (Figure 12.1) such as bortezomib,14 carfilzomib (PR-171)31 and CEP-187 70.30 These agents inhibit the CT-L activity to a similar degree as NPI-0052 but exhibit different inhibition profiles for the T-L and C-L activities. In addition, NPI-0052 exhibits a different recovery profile of proteasome functions in whole blood, normal organs, tumour and peripheral blood mononuclear cell preparations compared with other agents.52... 

Our studies clearly differentiate NPI-0052 from other proteasome inhibitors in the speed and duration of action and the inhibition profile of the 20S proteasome. These differences and the possible off-target activities of bortezomib indicate that NPI-0052 may provide a greater therapeutic index and greater activity in diseases where bortezomib shows minimal activity.64... 

Rflc-venlafaxine 10 and its sila analogue rac-11 have similar physicochemical properties (pi Ca = 9.7, log P = 3.1 in n-octanol/water, log P = 0.9 at pH 7.4) indicating that venlafaxine and sila-venlafaxine could have a similar brain penetration profile. The in vitro pharmacological studies of venlafaxine, sila-venlafaxine and their enantiomers (used as hydrochlorides) for their efficacy in monoamine reuptake inhibition demonstrated differences in activity and also in inhibition profile (06JOM(691)3589, 06OM1188). With respect to serotonin, noradrenaline and dopamine reuptake inhibition potency these... 

Casillas, R., Kam, C.M., Powers, J.C. (2000a). Serine and cysteine proteases in sulfur mustard-exposed hairless mouse skin enzymatic activity and inhibition profiles. J. Toxicol. Cutan. Ocul. Toxicol. 19 137-51. 

Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, Gar man EF, Gibson AE, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Lawrie AM, Newell DR, Noble ME, Sausville EA, Schultz R, Yu W. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 2000 43 2797-804. 

Barecki ME, Casciano CN, Johnson WW, Clement RP. In vitro characterization of the inhibition profile of lorata-dine, desloratadine, and 3-OH-desloratadine for five human cytochrome P-450 enzymes. Drug Metab Dispos 2001 29(9) 1173-5. 

Fig. 2. In vitro efficacy of compounds rac-Sa, rac-Sh, rac-6, and rac-1 regarding serotonin, noradrenaline, and dopamine reuptake inhibition. pICso denotes the negative decadic logarithm of the half-maximum effect concentration [M]. The monoamine reuptake inhibition profiles of rac-Sa, rac-5b, rac-6, and rac-1 were genoated via radioligand transporter assays using recombinant human monoamine transporter proteins. The data represent the mean of duplicate analyses.

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